5s02
NOTES
trates were adjusted to pH 2-3 with nitric acid; 25% AgSO3 was added till the precipitation was complete. The white silver salt was washed with water t o remove all excess HNOa and AgSOs. The silver salt was suspended in 35 ml. of mater and treated exhaustively with H2S. Silver sulfide was removed and the filtrate concentrated t o dryness in vucuo. The dried residue was crystallized from 3 ml. of nbutyl alcohol. The resulting product was collected by filtration, washed with petroleum ether and dried in vucuo a t 55' for 2 hours. One hundred twenty mg. of l-methyl-vtriazole-4,5-dicarboxylic acid, m.p. 174175" dec., was obtained. An additional 70 mg. of product could be obtained from the mother liquor by the careful addition of petroleum ether, m.p. 170" dec. 4 n d . Calcd. for C6HjO4X3: C, 35.09; H , 2.95; 0, 37.39; N, 24.56. Found: C, 35.02; H , 3.02; 0, 37.28; S.24.68. (b) Oxidation of I-methylbenzotria~ole~ was performed under ( a ) , n1.p. 175-176' dec.; mixture of l-methyl-vtriazole-4,5-dicarboxglic acid from (a) and (b), m.p. 174l 7 j 0 dec. INSTI? UTE FOR E X Z l M E RESEARCH USIVERSITY O F \l-ISCOSSIX MADISOS,~VISCUVSIS
Vol. 76
agreement of the boiling points, refractive indices, and infrared spectra established that the products obtained from these three diverse procedures were identical.
Experimental N-Methyl-2-pyrrolealdehyde .-The procedure which was used for the formylation of pyrrole' was applied t o 9methylpyrrole. The product was obtained in 25% yield; boiling point 73-75' (11 mm.), lit.4 75-76' (12 m m . ) ; semicarbazone 206-208", lit.6 207-208". A better yield was obtained from a simpler procedure based on the method of Rogers6 for the formylation of 2,4diphenylpyrrole with N-methylformanilide: To 7.3 g. of dimethylformamide in a flask fitted with a stirrer, condenser and drying tube, was added 17.8 g. of phosphorus oxychloride. After 10 minutes, the flask was placed in a 60" bath, and 4.1 g. of K-methylpyrrole was added dropwise over a period of 30 minutes. The mixture was stirred a t 60' for an additional hour, then poured on 100 g. of ice. Hydrolysis was completed by adding 75 g. of sodium acetate and heating the mixture just to boiling. The mixture was cooled and extracted with ether. The ether solution was washed with sodium carbonate, dried and evaporated, and the residue was distilled a t 73-75" a t 11 mm.; yield 2.7 g. (48%). Sodium Borohydride Reduction of N-Methyl-2-pyrroleN-Methyl-2-pyrrolealdehyde and N-Methyl-2-hy- aldehvde .-A solution of 2.0 g. of sodium borohvdride in 15 mi. of methyl alcohol was aaded portionwise t d a stirred droxyme thylpyrrole solution of 2.04 g. of N-methyl-2-pyrrolealdehyde in 10 ml. B Y EDU-ARD E. RYSKIEWICZ AND ROBERT M. SILVERSTEIN of methyl alcohol. The temperature was held below 55' by intermittent cooling. After one hour, 25 ml. of water RECEIVED JULY 6, 1954 was added. The solution was saturated with potassium The formylation of pyrrole with dimethylforma- carbonate, and extracted with ether. After the ether soluwas dried and the ether was removed, the residue was mide to give 2-pyrrolealdehyde, and the reduction tion distilled a t 98-100" a t 11 mm. The distillate was a modof the aldehyde to 2-hydroxymethylpyrrole, was erately viscous, colorless oil; yield 1.26 g. (61%). A?teZ. Calcd. for N-methyl-2-hydroxymethylpyrrole: C, 64.8; reported recently. H, 8.11; (R)D, 32.2. Found: C, 64.5; H , 8.11; ( R ) D A compound previously reported2 as 2-hydroxy- 31.9; 0 ~ d204 1.070. The infrared spectrum methylpyrrole was shown to be the pinacol formed showed ~ the2 1.5268, hydrogen-bonded hydroxyl band a t 3.00 p . by a bimolecular reduction of 2-pyrrolealdehyde. After two weeks in the refrigerator, the liquid crystallized. This communication records the formylation of Two recrystallizations from a petroleum ether-benzene mixgave white crystals melting a t 28-30". N-methylpyrrole with dimethylformamide to give tureHydrolysis of N-Methyl-2-dimethylaminomethylpyrrole i'l-methyl-2-pyrrolealdehyde, and the reduction of Methiodide .-The quaternary ammonium salt was prepared this aldehyde with sodium borohydride to the pre- as described by Herz and Rogers.? Attempted alkaline viously unreported N-methyl-2-hydroxymethyl- hydrolysis of this compound under the very mild conditions used by Leete and Marion3 for gramine methiodide was not pyrrole. The elemental analysis, molar refractiv- successful. The desired alcohol was obtained, albeit in poor ity and infrared spectrum were in accord with the yield, as follows: To a stirred refluxing mixture of 125 ml. postulated structure. A11 efforts, however, to pre- of 10% sodium hydroxide and 125 ml. of benzene pare a derivative of this simplest alcohol of the N- was added, over a period of 20 minutes, 7.0 g. of;y-methylmethiodide in l n ml. of methylpyrrole series were unsuccessful, as was also 2-dimethylaminomethylpyrrole water. After refluxing for an additional hour, the beiizene the case for 2-hydroxymethylpyrrole. Treatment layer was separated. The residue following evaporatiou with acetic anhydride in pyridine, benzoyl chloride of the benzene weighed 0.60 g. The aqueous alkaline soluand 2,4-dinitrobenzoyl chloride in pyridine and in tion was refluxed and stirred with another 125-ml. portion benzene for three hours. An additional 1.1 g. of residue ether with potassium carbonate, dilute aqueous of was thus extracted. Distillation of the combined residues potassium permanganate, picric acid, trinitroben- gave 0.30 g. (11%) of a moderately viscous oil which dis1.5268. The infrared spectrum zene, a-naphthyl isocyanate and triphenylmethyl- tilled a t 95" a t 11 mm., nZO~ chloride in pyridine gave polymeric material. Shak- was identical with that of the product obtained by sodium reduction of N-methyl-2-pyrrolealdehyde. ing an ether solution of the alcohol with aqueous so- borohydride Crossed-Cannizzaro Reaction of N-Methyl-Z-pyrrolealdedium bisulfite to remove traces of the aldehyde also hyde.-A procedure for the preparation of p-tolylcarbinol* resulted in polymerization of the alcohol. was adapted for our purpose: T o a solution of 3.0 g. of poUnequivocal proof of the identity of the alcohol tassium hydroxide in 6 ml. of methyl alcohol was added :L of 2.33 g. of N-methylpyrrolealdehyde and 2 ml. OF was obtained by preparing the same compound by mixture formalin (37% formaldehyde). The mixture mas allowed two other routes. The preparation of 3-hydroxy- to stand overnight a t room temperature, held a t 60" for methylindole by Leete and Marion3 by alkaline hy- one hour, diluted with 20 ml. of water, saturated with potasdrolysis of gramine methiodide led us successfully sium carbonate and extracted with ether. The ether was dried, the solvents removed and the residue was to apply this technique to the methiodide of N- solution distilled a t 11 mm. in a Claisen flask. A forerun of 1.0 g .
methyl-2-dimethylaminomethylpyrrole. h crossedCannizzarro reaction of K-methyl-2-pyrrolealdehyde yielded the same product. Satisfactory K. M. Silverstein, E. E . Ryskiewicz and
S. W. Chaikin, THIS 76, 4485 (1954). ( 2 ) 11. S.Taggart and G H. Richter, ibid., 66, 138; (1934). (3) E. Leete and L. Marion, Cali. J . C h e m . , 3 1 , 775 (1063).
(1)
JOURKAL,
(4) E . Fischer, B e y , 46, 2504 (1913).
(5) H. Fischer and H. Orth, "Die Chemie des I'yrrols," Vol I , Edwards B r o s , Ann Arbor, hlich., 1943, p. 175. (6) h l . A . T. Rogers, J . Chem.. SOL.,596 (1943). (7) W. Herz and J. L. Rogers, THISJOURNAL, 73, 4921 (1951). (8) "Organic Syntheses," Coll. Vol. 11, John Wiley and Sons, Inc., Nerr York, N. Y., 1943, p 590.
Nov. 20, 1954
NOTES
5803
cooling bath was removed after another 15 minutes, and the suspension stirred a t room temperature for one hour, then a t the refluxing temperature for another hour. It was filtered hot, and the solid washed with boiling benzene. The combined filtrate and washings were concentrated t o about 100 a 1. and cooled, providing 17.23 g . of colorless prismatic m.p. 123-126" (lit. 122-124',' 122.5-123.5O2). Acknowledgment.-The authors are indebted to needles, The product did not depress the melting point of a sample Miss C. Brown for the carbon and hydrogen de- prepared by Badgett's2 procedure. Another 2.09 g., m.p. terminations, and to Dr. H. J. Eding for the infrared 123", was obtained from the mother liquor by concentrating spectra. The sample of N-methylpyrrole was and adding hexane, bringing the total yield to 85%. Isonicotinic Anhydride.-The same procedure was used kindly furnished us by the Electrochemicals De- starting with potassium isonicotinate, except that after repartment of E. I. du Pont de Nemours & Co. moving the ice-bath the suspension was stirred a t room temperature for two hours, filtered, and the residue washed DEPARTMENT O F CHEMISTRY f i s t with cold benzene, then extracted with hot benzene. STANFORD RESEARCH INSTITUTE The combined light yellow filtrates were concentrated under STANFORD, CALIFORNIA reduced pressure t o about 100 ml. and diluted with an equal volume of hexane to yield $.56 g. (73%) of colorless elonRecrystallization from bengated prisms, m.p. 112-114 Preparation of Nicotinic and Isonicotinic An- zene-pentane brought the m.p. to 112.7-113.9'. The hydride analytical sample (same m.p.) was obtained by vacuum sublimation (bath 115'). BY ANTHONYW. SCHRECKER A N D PRISCILLA B. MAURY Anal. Calcd. for C12H803Nz: C, 63.16; H , 3.53; N, 12.28; sapn. equiv., 114. Found: C, 63.36; H , 3.43; N, JULY I, 1954 RECEIVED 12.47; sapn. equiv., 111. Nicotinic and isonicotinic anhydride were first In a preliminary experiment, the compound was obtained prepared by reaction of their acid chlorides with in the form of plates, m.p. 103-105° (1it.l rhombic prisms, their sodium salts.' The disadvantages of the m.p. 103-104'). Subsequent runs yielded the higherpolymorphic modification only. original method, which requires vacuum distilla- melting Preparations in which the suspension was refluxed as in tion of the acid chlorides, have been emphasized by the case of nicotinic anhydride gave essentially iden tical Badgett,* who published a simplified procedure for yields and melting points; the product was, however, conthe preparation of nicotinic anhydride, in which taminated with a trace of blue dye, which could be removed by treatment with Norit. The yield was not improved when the intermediary nicotinyl chloride was obtained 0.1 mole of potassium isonicotinate was allowed to react and used in situ. His procedure, however, in- with 0.1 mole of oxalyl chloride to produce isonicotinyl chlovolves the use of nitrobenzene, the last traces of ride in situ, followed by addition of another 0.1 mole of which are not readily removed from the product, potassium isonicotinate. and i t is furthermore inapplicable to isonicotinic LABORATORY O F CHEMICAL PHARMACOLOGY CANCERINSTITUTE anhydride, which is unstable' at the high tempera- NATIONAL NATIOKAL INSTITUTES OF HEALTH ture that must be employed. BETHESDA 14, MD.
was discarded. A cut weighing 0.56 g. was taken; it distilled a t 96-98', +OD 1.5330. The infrared spectrum showed that this cut was largely N-methyl-2-hydroxymethylpyrrole containing some of the unreacted aldehyde. On the basis of the refractive index, the material was 79% alcohol.
.
More recently, a new procedure for the preparation of nicotinyl chloride has been described,3 in which oxalyl chloride is substituted for the previously employed2s4thionyl chloride. Since hydrogen chloride is not formed under these conditions, nicotinyl chloride is obtained directly, and decomposition by distillation from pyridine4 or by pyrolysis2of the nicotinyl chloride hydrochloride produced in the presence of thionyl chloride becomes unnecessary. Wingfield's procedure is an application of a general reaction discovered by Adams and Ulich,6 who showed that sodium salts of organic acids react with oxalyl chloride to yield either acid chlorides or acid anhydrides, depending on the molar proportions of the reagents. By modifying Wingfield's procedure in the light of these findings, a very convenient and rapid method for preparing directly both nicotinic and isonicotinic anhydride has been developed in this Laboratory. Experimental Nicotinic Anhydride.-To a suspension of 32.24 g. (0.2 mole) of potassium nicotinate, which had been ground to pass a 100-mesh sieve and dried a t 135°,s in 80 ml. of anhydrous benzene was added, with mechanical stirring and cooling in an ice-bath, 12.69 g. (0.1 mole) of oxalyl chloride in 45 ml. of anhydrous benzene during 20 minutes. The (1) R. Graf, Biochem. Z.,2 2 9 , 164 (1930). (2) C. 0.Badgett, THISJOURNAL, 69, 2231 (1947). (3) H.N. Wingfield, Jr., W. R. Harlan and H. R. Hanmer, ibid., 76, 4364 (1953). (4) H.Meyer and R.Graf, Ber., 61, 2202 (1928). ( 5 ) R. Adams and L. H . Ulich, THISJOURNAL, 4 2 , 599 (1920): cf. I
